Buprenorphine has been proposed as a pharmacotherapeutic agent in the treatment of opiate addiction. This drug may serve to decrease HIV transmission risk behaviors among intravenous opioid abusers. Although it is currently marketed in the United States as an analgesic, its use in drug abuse treatment is investigational. This study is designed to facilitate approval of buprenorphine for use in treatment opioid- dependent subjects. The pharmacological profile of buprenorphine is similar to that of morphine at low doses, but at higher sublingual doses, a ceiling effect has been noted with many of buprenorphine's effects, including respiratory depression. Long-term treatment and detoxification of heroin-dependent subjects with buprenorphine requires regular (daily or less often) medication. Initial studies were designed to evaluate the pharmacologic and pharmacodynamic profile of buprenoprhine when administered by the sublingual and buccal routes compared to the intravenous route. Plasma samples were collected up to 96 hours and assayed for buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry. Buprenorphine bioavailability by the sublingual and buccal routes was estimated as 51.4% and 27.8%, respectively, although there was considerable inter-subject variability by both routes of administration. The terminal elimination half-lives were longer for the sublingual and buccal routes than the intravenous route. The extended elimination half-lives may be due to a shallow depot effect by sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean peak plasma concentrations were less than 1 ng/mL and were highly variable between different routes of administration and subjects. The terminal elimination half-life of norbuprenorphine was longer than buprenorphine. Further studies are underway to evaluate buprenorphine doses in the range of those used for maintenance, evaluate buprenorphine's abuse liability by the IV route, determine whether a ceiling occurs on the effects of intravenously administered buprenorphine, provide a basis for calculating the relative potencies of sublingual and IV buprenorphine at high doses, and determine levels of buprenorphine and morphine in blood, sweat, and hair. The results of these studies will add vital information needed to establish policies regarding the use of buprenorphine in clinical practice and to evaluate the consequences to those who obtain and self-administer diverted buprenorphine maintenance doses.